This is a continuing renewal of our R01 previously titled "Functional MRl for Early Diagnosis of Alzheimer's Disease" (5 R01 AG013308-10). The proposed third grant cycle builds on recent findings from this project and new technologies we have developed for imaging hippocampal structure and function. Our data support the utility of combining genetic risk, structural and functional MRl to identify early manifestations of Alzheimer's disease (AD), and further suggest that brain changes may occur much earlier than previously thought in Apolipoprotein epsilon-4 (APOE-4) carriers. Recently, our group has developed new techniques in high-resolution functional MRl acquisition and analysis, and in mathematical modeling algorithms that identify structural MRl change in Alzheimer's disease subjects over very short time periods. In addition, our group has recently worked with positron emission tomography (PET) using [18F]MPPF imaging, a ligand that measures pyramidal cell density in the hippocampus (HC), entorhinal cortex and amygdala;our preliminary data show that [18F]MPPF binding is decreased in MCI and AD, and correlates with memory in healthy controls, suggesting its potential as an independent assessment of risk for AD. This grant proposes using a combination of four new imaging techniques, two structural (HC cortical thickness and HC radial atrophy), and two functional (FMRI and [18F]MPPF) in control subjects in the 40-80 range at-risk for AD and MCI patients, to determine if there are subtle longitudinal changes in HC structure and function similar to those seen in AD, in cognitively intact at-risk subjects in the late middle age to elderly range. We will recruit 60 younger (40-60) and 36 older (60+) controls, (50% of each with APOE-4), and 35 mild MCI subjects, and follow them for 21/2 years using these novel imaging measures and clinical assessments. Analyses will focus on modeling the rate of change of each measure alone and in combination, with the goal of identifying subjects at highest risk for developing AD. Diagnostic and neuropsychological evaluations will provide clinical corroboration that genotype, family history, and short-term brain changes predict cognitive decline. By combining these different measures of hippocampal structure and function, our primary goal is to develop an approach to identifying those at-risk who are more likely to develop AD, and to determine which of these novel imaging techniques provide the most optimal and independent predictors of future decline.